A number of proposals have been advanced for oxygen transport systems as a temporary substitute, or partial substitute for the natural oxygen carrying red blood cells in mammals. Temporary disfunction, violent trauma and other mishaps or accidents sometimes require a substitute or at least partial substitute for the blood cells. In many instances whole blood is unavailable, or if available, may be of the incorrect type. Plasma, if available, aids in maintaining circulatory volume, but it is devoid of any oxygen carrying component. Thus the development of artificial resuscitative fluids have been investigated for a number of years, but to date no universally acceptable product has yet been approved.
Basically an artificial resuscitative fluid should have the following properties to be feasible:
It should function for at least several hours as well as normal blood having a hematocrit of about 15-20%.
It should not be toxic.
It should be sterile and pyrogen free.
It should be free of any antigens, i.e., it should not activate the body's immune system; nor should it require any blood typing analysis.
It should have a reasonable "shelf-life" at least as long as, or longer than, fresh whole blood.
Many different approaches have been made in providing a viable oxygen transport system. One generally promising approach utilizes fluorocarbon emulsions. Such emulsions are capable dissolving oxygen in the non-aqueous phase, and under the proper conditions, releasing it to the surrounding tissues. Although fluorocarbon emulsions are themselves biologically acceptable from an antigen-free standpoint, they are subject to removal from circulation by the reticuloendothelial system (RES) which is part of the body's immune defense mechanism. Inert colloidals such as fluorocarbon emulsions, if removed with facility by the reticuloendothelial system may produce a "blockade" of the RES. More specifically, RES cells function to remove bacteria, viruses and many other particulates from the circulation. If the RES cells are overloaded by a large dose of particulates, as would be the case in the infusion of a fluorocarbon emulsion, they "shut down" and temporarily cease to function, or function at greatly reduced capacity. In this state, the body is quite susceptible to infection. Many emulsions are known to cause this "RES blockade".
In another approach, liposome technology has been employed. Liposomes are small vesicles comprising one or more concentric lipid bilayer spheres enclosing an interior space or spaces. These spaces may contain any water soluble active agent, which will be transported in the liposomes and released therefrom under certain conditions. In the present instance, oxygen transport systems comprising liposomes encapsulating the normal hemoglobin containing aqueous contents of red cells have been utilized as artificial resuscitative fluids. However, liposomes having a resemblance to emulsions, are also primarily removed from circulation by the reticuloendothelial system. Thus the liposome approach is subject to many of the problems associated with fluorocarbon emulsions.
In addition, hemoglobin is a relatively fragile material which is easily degraded by elevated temperatures, contact with oxidizing and reducing agents, and any severe handling procedures. Any denaturization of hemoglobin itself, or the presence of hemoglobin degradation products are undesirable in an artificial oxygen transport system. Such products are also readily taken up by the RES, since they tend to be antigenic and exhibit immunogenic properties. While the total content of natural red blood cells would also appear as being ideal for inclusion in an artificial oxygen transport system, quite the opposite is the case. The various proteins and enzymes within the red blood cell can become incorporated into any lipid membrane into which the cell contents are placed. These proteins and enzymes induce antigenic, immunogenic, and adverse blood clotting reactions. Thus oxygen transport systems incorporating hemoglobin degradation products, or proteins and enzymes from natural red blood cells are rapidly cleared from the circulatory system. The amount of the oxygen transport system in circulation therefore quickly decreases and the oxygen transport effectiveness disappears. At the same time, the rapid uptake by the RES, may produce "RES blockade" with its concomitant undesirable effects on the body.
An artifical oxygen transport system has now been devised that overcomes the problems set forth above.